Abnormal gamma phase-amplitude coupling in the parahippocampal cortex is associated with network hyperexcitability in Alzheimer's disease.

While animal models of Alzheimer's disease (AD) have shown altered gamma oscillations (∼40 Hz) in local neural circuits, the low signal-to-noise ratio of gamma in the resting human brain precludes its quantification via conventional spectral estimates. Phase-amplitude coupling (PAC) indicating the dynamic integration between the gamma amplitude and the phase of low-frequency (4-12 Hz) oscillations is a useful alternative to capture local gamma activity. In addition, PAC is also an index of neuronal excitability as the phase of low-frequency oscillations that modulate gamma amplitude, effectively regulates the excitability of local neuronal firing. In this study, we sought to examine the local neuronal activity and excitability using gamma PAC, within brain regions vulnerable to early AD pathophysiology-entorhinal cortex and parahippocampus, in a clinical population of patients with AD and age-matched controls. Our clinical cohorts consisted of a well-characterized cohort of AD patients (n = 50; age, 60 ± 8 years) with positive AD biomarkers, and age-matched, cognitively unimpaired controls (n = 35; age, 63 ± 5.8 years). We identified the presence or the absence of epileptiform activity in AD patients (AD patients with epileptiform activity, AD-EPI+, n = 20; AD patients without epileptiform activity, AD-EPI-, n = 30) using long-term electroencephalography (LTM-EEG) and 1-hour long magnetoencephalography (MEG) with simultaneous EEG. Using the source reconstructed MEG data, we computed gamma PAC as the coupling between amplitude of the gamma frequency (30-40 Hz) with phase of the theta (4-8 Hz) and alpha (8-12 Hz) frequency oscillations, within entorhinal and parahippocampal cortices. We found that patients with AD have reduced gamma PAC in the left parahippocampal cortex, compared to age-matched controls. Furthermore, AD-EPI+ patients showed greater reductions in gamma PAC than AD-EPI- in bilateral parahippocampal cortices. In contrast, entorhinal cortices did not show gamma PAC abnormalities in patients with AD. Our findings demonstrate the spatial patterns of altered gamma oscillations indicating possible region-specific manifestations of network hyperexcitability within medial temporal lobe regions vulnerable to AD pathophysiology. Greater deficits in AD-EPI+ suggests that reduced gamma PAC is a sensitive index of network hyperexcitability in AD patients. Collectively, the current results emphasize the importance of investigating the role of neural circuit hyperexcitability in early AD pathophysiology and explore its potential as a modifiable contributor to AD pathobiology.

Factors associated with preoperative and postoperative seizures in patients undergoing resection of brain metastases.

OBJECTIVE: Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors. METHODS: Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures. RESULTS: Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively. CONCLUSIONS: Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion-targeting therapeutic interventions on seizure control in these patients.

Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer's disease.

Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer's disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer's disease. Using magnetoencephalography (MEG) at rest, we studied 30 Alzheimer's disease patients without subclinical epileptiform activity, 20 Alzheimer's disease patients with subclinical epileptiform activity and 35 age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with Alzheimer's disease by long-term video-EEG and a 1-h resting MEG with simultaneous EEG. Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillatory frequencies. We found that Alzheimer's disease patients with subclinical epileptiform activity have greater reductions in alpha imaginary coherence and greater enhancements in delta-theta imaginary coherence than Alzheimer's disease patients without subclinical epileptiform activity, and that these changes can distinguish between Alzheimer's disease patients with subclinical epileptiform activity and Alzheimer's disease patients without subclinical epileptiform activity with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini-Mental State Examination in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next-generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction together with cognitive and clinical correlates in patients with Alzheimer's disease.

Direct and indirect costs associated with stereotactic radiosurgery or open surgery for medial temporal lobe epilepsy: Results from the ROSE trial.

OBJECTIVE: To determine whether a less-invasive approach to surgery for medically refractory temporal lobe epilepsy is associated with lower health care costs and costs of lost productivity over time, compared to open surgery. METHODS: We compared direct medical costs and indirect productivity costs associated with treatment with stereotactic radiosurgery (SRS) or anterior temporal lobectomy (ATL) in the ROSE (Radiosurgery or Open Surgery for Epilepsy) trial. Health care use was abstracted from hospital bills, the study database, and diaries in which participants recorded health care use and time lost from work while seeking care. Costs of use were calculated using a Medicare costing approach used in a prior study of the costs of ATL. The power of many analyses was limited by the sample size and data skewing. RESULTS: Combined treatment and follow-up costs (in thousands of US dollars) did not differ between SRS (n = 20, mean = $76.6, 95% confidence interval [CI] = 50.7-115.6) and ATL (n = 18, mean = $79.0, 95% CI = 60.09-103.8). Indirect costs also did not differ. More ATL than SRS participants were free of consciousness-impairing seizures in each year of follow-up (all P < 0.05). Costs declined following ATL (P = 0.005). Costs tended to increase over the first 18 months following SRS (P = 0.17) and declined thereafter (P = 0.06). This mostly reflected hospitalizations for SRS-related adverse events in the second year of follow-up. SIGNIFICANCE: Lower initial costs of SRS for medial temporal lobe epilepsy were largely offset by hospitalization costs related to adverse events later in the course of follow-up. Future studies of less-invasive alternatives to ATL will need to assess adverse events and major costs systematically and prospectively to understand the economic implications of adopting these technologies.

Visual field defects after radiosurgery versus temporal lobectomy for mesial temporal lobe epilepsy: Findings of the ROSE trial.

PURPOSE: Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9-100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ. METHODS: This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated. RESULTS: No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status. CONCLUSION: The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method.

Radiosurgery versus open surgery for mesial temporal lobe epilepsy: The randomized, controlled ROSE trial.

OBJECTIVE: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). METHODS: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. RESULTS: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. SIGNIFICANCE: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia.

SEE SCABER AND TALBOT DOI101093/AWW264 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: A GGGGCC repeat expansion in C9orf72 leads to frontotemporal dementia and/or amyotrophic lateral sclerosis. Diverse pathological features have been identified, and their disease relevance remains much debated. Here, we describe two illuminating patients with frontotemporal dementia due to the C9orf72 repeat expansion. Case 1 was a 65-year-old female with behavioural variant frontotemporal dementia accompanied by focal degeneration in subgenual anterior cingulate cortex, amygdala, and medial pulvinar thalamus. At autopsy, widespread RNA foci and dipeptide repeat protein inclusions were observed, but TDP-43 pathology was nearly absent, even in degenerating brain regions. Case 2 was a 74-year-old female with atypical frontotemporal dementia-motor neuron disease who underwent temporal lobe resection for epilepsy 5 years prior to her first frontotemporal dementia symptoms. Archival surgical resection tissue contained RNA foci, dipeptide repeat protein inclusions, and loss of nuclear TDP-43 but no TDP-43 inclusions despite florid TDP-43 inclusions at autopsy 8 years after first symptoms. These findings suggest that C9orf72-specific phenomena may impact brain structure and function and emerge before first symptoms and TDP-43 aggregation.

Incidence and impact of subclinical epileptiform activity in Alzheimer's disease.

OBJECTIVE: Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition. METHODS: We prospectively enrolled 33 patients (mean age, 62 years) who met criteria for AD, but had no history of seizures, and 19 age-matched, cognitively normal controls. Subclinical epileptiform activity was assessed, blinded to diagnosis, by overnight long-term video-electroencephalography (EEG) and a 1-hour resting magnetoencephalography exam with simultaneous EEG. Patients also had comprehensive clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years. RESULTS: Subclinical epileptiform activity was detected in 42.4% of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such activity. However, patients with subclinical epileptiform activity showed faster declines in global cognition, determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01). INTERPRETATION: Extended monitoring detects subclinical epileptiform activity in a substantial proportion of patients with AD. Patients with this indicator of network hyperexcitability are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for more sensitive and comprehensive neurophysiological assessments in AD patient evaluations and impending clinical trials. Ann Neurol 2016;80:858-870.

Corpus callosotomy versus vagus nerve stimulation for atonic seizures and drop attacks: A systematic review.

Atonic seizures are debilitating and poorly controlled with antiepileptic medications. Two surgical options are primarily used to treat medically refractory atonic seizures: corpus callosotomy (CC) and vagus nerve stimulation (VNS). However, given the uncertainty regarding relative efficacy and surgical complications, the best approach for affected patients is unclear. The PubMed database was queried for all articles describing the treatment of atonic seizures and drop attacks with either corpus callosotomy or VNS. Rates of seizure freedom, >50% reduction in seizure frequency, and complications were compared across the two patient groups. Patients were significantly more likely to achieve a >50% reduction in seizure frequency with CC versus VNS (85.6% versus 57.6%; RR: 1.5; 95% CI: 1.1-2.1). Adverse events were more common with VNS, though typically mild (e.g., 22% hoarseness and voice changes), compared with CC, where the most common complication was the disconnection syndrome (13.2%). Both CC and VNS are well tolerated for the treatment of refractory atonic seizures. Existing studies suggest that CC is potentially more effective than VNS in reducing seizure frequency, though a direct study comparing these techniques is required before a definitive conclusion can be reached.

Unilateral holohemispheric central nervous system lesions associated with medically refractory epilepsy in the pediatric population: a retrospective series of hemimegalencephaly and Rasmussen's encephalitis.

OBJECT: Cortical malformations and inflammatory encephalopathy are among common etiologies for medically refractory epilepsy in children. On rare occasions, lesions can affect an entire cerebral hemisphere while sparing the other; the 2 processes that can manifest in this manner are hemimegalencephaly (HME) and Rasmussen's encephalitis (RE). Although the clinical course and radiological appearance between the 2 disorders are distinct, there is occasional overlapping pathology between RE and cortical migration disorders. One question that arises from these observations is whether RE and HME, diseases with holohemispheric involvement but apparently different etiologies, have any overlapping characteristics. METHODS: The authors performed a retrospective review of all patients with presumed diagnosis of HME or RE who underwent hemispherectomy at University of California, San Francisco, and reviewed their clinical presentation, imaging, and pathology data. RESULTS: The authors present the clinicopathological features of 14 pediatric patients with unilateral holohemispheric lesions associated with medically refractory epilepsy. Radiological and pathological assessment classified 7 of the patients as having hemimegalencephaly, while the other 7 were diagnosed as having RE. Four of the patients had unusual features suggestive of overlapping developmental and inflammatory (dual) pathology. All patients underwent hemispherectomies. Eight patients (57%) became seizure free (Engel Class I), 5 patients (36%) had rare seizures (Engel Class II), and 1 patient had significant seizure reduction (Engel Class III). CONCLUSIONS: Based on this case series, HME and RE can be distinguished on the basis of their radiological and histological appearance, even though some cases may have overlapping features. Hemispherectomy was effective at eliminating seizures for both HME and RE.

Factors associated with failed focal neocortical epilepsy surgery.

BACKGROUND: Seizure outcomes after focal neocortical epilepsy (FNE) surgery are less favorable than after temporal lobectomy, and the reasons for surgical failure are incompletely understood. Few groups have performed an in-depth examination of seizure recurrences to identify possible reasons for failure. OBJECTIVE: To elucidate factors contributing to FNE surgery failures. METHODS: We reviewed resections for drug-resistant FNE performed at our institution between 1998 and 2011. We performed a quantitative analysis of seizure outcome predictors and a detailed qualitative review of failed surgical cases. RESULTS: Of 138 resections in 125 FNE patients, 91 (66%) resulted in freedom from disabling seizures (Engel I outcome). Mean ± SEM patient age was 20.0 ± 1.2 years; mean follow-up was 3.8 years (range, 1-17 years); and 57% of patients were male. Less favorable (Engel II-IV) seizure outcome was predicted by higher preoperative seizure frequency (odds ratio = 0.85; 95% confidence interval, 0.78-0.93), a history of generalized tonic-clonic seizures (odds ratio = 0.42; 95% confidence interval, 0.18-0.97), and normal magnetic resonance imaging (odds ratio = 0.30; 95% confidence interval, 0.09-1.02). Among 36 surgical failures examined, 26 (72%) were related to extent of resection, with residual epileptic focus at the resection margins, whereas 10 (28%) involved location of resection, with an additional epileptogenic zone distant from the resection. Of 16 patients who received reoperation after seizure recurrence, 10 (63%) achieved seizure freedom. CONCLUSION: Insufficient extent of resection is the most common reason for recurrent seizures after FNE surgery, although some patients harbor a remote epileptic focus. Many patients with incomplete seizure control are candidates for reoperation.

Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study.

BACKGROUND: Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications. METHODS: Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach. RESULTS: A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations. CONCLUSION: This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.

Seizures and epileptiform activity in the early stages of Alzheimer disease.

IMPORTANCE: Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease. OBJECTIVE: To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity. DESIGN: Retrospective observational study from 2007 to 2012. SETTING Memory and Aging Center, University of California, San Francisco. PATIENTS: We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7). MAIN OUTCOMES AND MEASURES: Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications. RESULTS: Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin. CONCLUSIONS AND RELEVANCE: Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

Seizure types and frequency in patients who "fail" temporal lobectomy for intractable epilepsy.

BACKGROUND: Temporal lobectomy can lead to favorable seizure outcomes in medically-refractory temporal lobe epilepsy (TLE). Although most studies focus on seizure freedom after temporal lobectomy, less is known about seizure semiology in patients who "fail" surgery. Morbidity differs between seizure types that impair or spare consciousness. Among TLE patients with seizures after surgery, how does temporal lobectomy influence seizure type and frequency? OBJECTIVE: To characterize seizure types and frequencies before and after temporal lobectomy for TLE, including consciousness-sparing or consciousness-impairing seizures. METHODS: We performed a retrospective longitudinal cohort study examining patients undergoing temporal lobectomy for epilepsy at our institution from January 1995 to August 2010. RESULTS: Among 241 TLE patients who received temporal lobectomy, 174 (72.2%) patients achieved Engel class I outcome (free of disabling seizures), including 141 (58.5%) with complete seizure freedom. Overall seizure frequency in patients with persistent postoperative seizures decreased by 70% (P < .01), with larger reductions in consciousness-impairing seizures. While the number of patients experiencing consciousness-sparing simple partial seizures decreased by only 19% after surgery, the number of individuals having consciousness-impairing complex partial seizures and generalized tonic-clonic seizures diminished by 70% and 68%, respectively (P < .001). Simple partial seizure was the predominant seizure type in 19.1% vs 37.0% of patients preoperatively and postoperatively, respectively (P < .001). Favorable seizure outcome was predicted by a lack of generalized seizures preoperatively (odds ratio 1.74, 95% confidence interval 1.06-2.86, P < .5). CONCLUSION: Given important clinical and mechanistic differences between seizures with or without impairment of consciousness, seizure type and frequency remain important considerations in epilepsy surgery.

Distinguishing language and race disparities in epilepsy surgery.

This study aimed to identify whether race/ethnicity and limited English proficiency impact the likelihood of pursuing surgical treatment for medically refractory epilepsy. We conducted a retrospective cohort study of 213 patients with medically refractory epilepsy and mesial temporal sclerosis who were being considered for temporal lobectomy between January 1, 1993 and December 31, 2010 with follow-up through December 31, 2012. Demographic and clinical factors potentially associated with surgical utilization, including self-reported race/ethnicity and preferred language, were gathered from the medical record. Patients of Asian/Pacific Islander or African American race were significantly less likely to pursue surgical treatment of epilepsy compared with non-Hispanic whites in a multivariate logistic regression model (adjusted for nonconcordant ictal EEG, age, and limited English proficiency) (OR 0.20, p=0.003; OR 0.15, p=0.001, respectively). Limited English proficiency was also significantly associated with lower odds of surgery (OR 0.38, p=0.034). Both race and limited English proficiency contribute to disparities in the surgical management of medically refractory epilepsy, especially among Asian/Pacific Islanders and African Americans. Culturally sensitive patient-physician communication and patient education materials might aid in surgical decision-making among minority groups.

Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease.

An important mechanism for large-scale interactions between cortical areas involves coupling between the phase and the amplitude of different brain rhythms. Could basal ganglia disease disrupt this mechanism? We answered this question by analysis of local field potentials recorded from the primary motor cortex (M1) arm area in patients undergoing neurosurgery. In Parkinson disease, coupling between ß-phase (13-30 Hz) and γ-amplitude (50-200 Hz) in M1 is exaggerated compared with patients with craniocervical dystonia and humans without a movement disorder. Excessive coupling may be reduced by therapeutic subthalamic nucleus stimulation. Peaks in M1 γ-amplitude are coupled to, and precede, the subthalamic nucleus ß-trough. The results prompt a model of the basal ganglia-cortical circuit in Parkinson disease incorporating phase-amplitude interactions and abnormal corticosubthalamic feedback and suggest that M1 local field potentials could be used as a control signal for automated programming of basal ganglia stimulators.

Relationship between hospital surgical volume, lobectomy rates, and adverse perioperative events at US epilepsy centers.

OBJECT: Epilepsy surgery remains significantly underutilized. The authors recently reported that the number of lobectomies for localized intractable epilepsy in the US has not changed despite the implementation of clear evidence-based guidelines 10 years ago supporting early referral for surgery. To better understand why epilepsy surgery continues to be underused, the authors' objective was to carefully examine hospital-related factors related to the following: 1) where patients are being admitted for the evaluation of epilepsy, 2) rates of utilization for surgery across hospitals, and 3) perioperative morbidity between hospitals with low versus high volumes of epilepsy surgery. METHODS: The authors performed a population-based cohort study of US hospitals between 1990 and 2008 using the Nationwide Inpatient Sample (NIS), stratifying epilepsy surgery rates and trends as well as perioperative morbidity rates by hospital surgical volume. RESULTS: The number of lobectomies for epilepsy performed at high-volume centers (> 15 lobectomies/year) significantly decreased between 1990 and 2008 (F = 20.4, p < 0.001), while significantly more procedures were performed at middle-volume hospitals (5-15 lobectomies/year) over time (F = 16.1, p < 0.001). No time trend was observed for hospitals performing fewer than 5 procedures per year. However, patients admitted to high-volume centers were significantly more likely to receive lobectomy than those at low-volume hospitals (relative risk 1.05, 95% CI 1.03-1.08, p < 0.001). Also, the incidence of perioperative adverse events was significantly higher at low-volume hospitals (12.9%) than at high-volume centers (6.1%) (relative risk 1.08, 95% CI 1.03-1.07, p < 0.001). CONCLUSIONS: Hospital volume is an important predictor of epilepsy surgery utilization and perioperative morbidity. Patients with medically refractory epilepsy should be referred to a comprehensive epilepsy treatment center for surgical evaluation by an experienced clinical team.

Transmantle sign in focal cortical dysplasia: a unique radiological entity with excellent prognosis for seizure control.

OBJECT: Focal cortical dysplasia (FCD) represents a spectrum of developmental cortical abnormalities and is one of the most common causes of intractable epilepsy in children and young adults. Outcomes after surgery for FCD are highly variable, and prognosticators of seizure freedom are unclear. In a subset of FCDs, a transmantle sign is observed on imaging that focally spans the entire cerebral mantle from the ventricle to the cortical surface. The aim of this study was to characterize seizure control outcomes and prognostic significance of the transmantle sign in FCD epilepsy. METHODS: Fourteen patients with the transmantle sign underwent epilepsy surgery for medically refractory epilepsy. Thirteen patients underwent resective surgery and 1 underwent multiple subpial transections with vagus nerve stimulator placement. Patient demographics, MRI, electroencephalography, intraoperative electrocorticography (ECoG), and pathology were reviewed. The results of this series were compared with those of 114 previously reported patients with FCD without the transmantle sign. RESULTS: All patients were found to have childhood seizure onset and concordant MRI and ECoG findings. The primary MRI findings associated with transmantle sign included gray-white junction blurring, appearance of cortical thickening, T2 or FLAIR abnormality, and bottom-of-the-sulcus dysplasia. The transmantle sign was usually a focal finding, typically confined to 1 or several gyri with well-circumscribed epileptic tissue. Correlation of the transmantle sign with FCD histopathological subtypes was highly variable. Patients who underwent complete resection of MRI and ECoG abnormalities (12 of 13 patients) became seizure free. When compared with 114 FCD patients without the transmantle sign, patients with the transmantle sign showed significantly improved seizure-free outcomes after complete resections (p = 0.04). CONCLUSIONS: The presence of the transmantle sign in patients with medically refractory partial epilepsy is associated with highly favorable seizure control outcomes after surgical treatment.

Seizure exacerbation in two patients with focal epilepsy following marijuana cessation.

While animal models of epilepsy suggest that exogenous cannabinoids may have anticonvulsant properties, scant evidence exists for these compounds' efficacy in humans. Here, we report on two patients whose focal epilepsy was nearly controlled through regular outpatient marijuana use. Both stopped marijuana upon admission to our epilepsy monitoring unit (EMU) and developed a dramatic increase in seizure frequency documented by video-EEG telemetry. These seizures occurred in the absence of other provocative procedures, including changes to anticonvulsant medications. We review these cases and discuss mechanisms for the potentially anticonvulsant properties of cannabis, based on a review of the literature.

Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo.

INTRODUCTION: Increasing evidence suggests the role of inflammation in enhancing neuronal excitability and contributing to epileptogenesis. Tetracycline-class antibiotics minocycline, doxycycline and tetracycline have been shown to have anti-apoptotic and anti-inflammatory effects. METHODS: We investigated the anti-seizure effects of tetracycline-class antibiotics minocycline, doxycycline and tetracycline in vivo by using the maximal electric shock (MES), 6-Hz (minimal clonic seizure) test and subcutaneous Metrazol (scMET) models of epilepsy. RESULTS: Minocycline, doxycycline and tetracycline showed anticonvulsant effects in abolishing partial seizures in the mouse 6-Hz seizure test. A dose-dependent effect was found, with ED(50) of 170 mg/kg for minocycline, 157 mg/kg for doxycycline, and 255 mg/kg for tetracycline with peak onset at 0.5h. At high doses, minocycline (250 mg/kg) and doxycycline (150 mg/kg) also had toxic effects, from motor impairments to respiratory failure and death. These drugs had no effects on the MES and scMET tests. CONCLUSIONS: In the three tests of anti-seizure activity, minocycline, doxycycline, and tetracycline were found to be protective in one: the 6-Hz seizure model. Our data suggest that minocycline and other tetracycline-class drugs may offer some degree of anticonvulsant effect in the setting of CNS disease trials.